title: MGAT3 mRNA: a biomarker for prognosis and therapy of Alzheimer's disease by vitamin D and curcuminoids.
abstract: Practical biomarkers of Alzheimer's disease (AD) prognosis are lacking. Correspondingly, no drugs are known to decrease disease progression, although vitamin D3 has positive effects on cognition in vivo and 1α, 25-dihydroxyvitamin D3 (1,25 D3) on amyloid-β 1-42 (Aβ) phagocytosis in vitro. We have examined in a pilot study a new biomarker in peripheral blood mononuclear cells, the transcription of mRNA of β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase (MGAT3), the essential gene for Aβ phagocytosis. The transcription of MGAT3 stimulated by Aβ distinguishes macrophages into Type 0 (very low MGAT3 transcription), Type I (low MGAT3 transcription up regulated by bisdemethoxycurcumin), and Type II (high MGAT3 transcription down regulated by bisdemethoxycurcumin). In this pilot study of 20 AD patients and 20 control subjects, 45% patients, but only 10% control subjects, were Type 0 (p-value = 0.009). Type 0 AD patients had worse 2-year prognosis regarding loss of independence than Type I and Type II patients (p-value = 0.013). Phagocytosis of Aβ in Type I and II patients was shown to be dependent on 1,25 D3 using a specific inhibitor of the 1,25 D3-VDR activated nuclear receptor transcription factor. In a Type II patient, recovery from cognitive dysfunction related to surgical anesthesia was preceded by an improvement in phagocytosis of Aβ. The results of this pilot study suggest that the MGAT3 Type biomarker may characterize subgroups of AD patients with different disease progression. In vitro results suggest that vitamin D3 supplementation might be beneficial in both Type I and II patients, whereas curcuminoids only in Type I. These results must be investigated in a large prospective study.
authors.affiliation: Department of Medicine, Greater Los Angeles VA Medical Center and UCLA School of Medicine, Los Angeles, CA, USA. fiala@mednet.ucla.edu
authors.forename: Milan
authors.initials: M
authors.lastname: Fiala
authors.forename: Michelle
authors.initials: M
authors.lastname: Mahanian
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenthal
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Mizwicki
authors.forename: Eric
authors.initials: E
authors.lastname: Tse
authors.forename: Tiffany
authors.initials: T
authors.lastname: Cho
authors.forename: James
authors.initials: J
authors.lastname: Sayre
authors.forename: Rachel
authors.initials: R
authors.lastname: Weitzman
authors.forename: Verna
authors.initials: V
authors.lastname: Porter
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003474:Curcumin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis / Q000235:genetics*; D010865:Pilot Projects; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis*; D014807:Vitamin D / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D014807:Vitamin D; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase; D003474:Curcumin